Synaptic N-methyl-D-aspartic acid (NMDA) receptors (NMDARs), composed, in large part, of NR2A-containing NMDARs (NR2ARs), promote cell survival, whereas extrasynaptic NMDARs, NR2B-containing NMDARs (NR2BRs), induce cell death. It is known that a host of macrophage inflammatory and viral products engage NMDARs, but there is very limited information available on how these receptors can be best utilized for optimal therapeutic benefit. To this end we seek funds to assess the role of HIV-1-infected and immune competent mononuclear phagocytes (MPs, brain perivascular macrophages and microglia) to affect extrasynaptic NR2BRs. MPs are the natural virus target cells and the key to neuronal dysfunction in HIV-1- associated neurocognitive disorders (HAND). Immunocytochemical, pharmacological and electrophysiological techniques will examine the role of extrasynaptic NR2BRs in HIV-1 infected MP-induced neuronal dysfunction and resultant cognitive impairment in laboratory and animal models of human disease. First, we will examine direct activation of NR2BRs by HIV-1 infected MP and resultant neurotoxic activity. Second, we will investigate the role of NR2BRs in HIV-1 infected MP-induced alteration of synaptic transmission and plasticity. Third, we will study whether HIV-1 infected MP-induced, NR2BR-mediated alteration of cellular and synaptic physiology contributes to HAND, and to explore potential protective effects of NR2BR antagonists in a relevant murine model of HIV disease. Overall, these studies are focused toward not only understanding the role that the subtype and location of NMDARs might play in HAND, but also on developing more realistic means to harness these pathways for therapeutic benefit. If successful, these studies will provide a proper roadmap for expected efficacy of NMDAR antagonists in ameliorating brain injury. PUBLIC HEALTH RELEVANCE: Synaptic N-methyl-D-aspartic acid (NMDA) receptors (NMDARs), composed, in large part, of NR2A-containing NMDARs (NR2ARs), promote cell survival, whereas extrasynaptic NMDARs, NR2B-containing NMDARs (NR2BRs), induce cell death. This proposal investigates how HIV-1-infected mononuclear phagocytes (brain macrophages and microglia) activate neuronal extrasynaptic NR2BRs, leading to neuronal damage and ultimately neurocognitive dysfunction. By completion of the proposed studies we will not only provide new insights into the mechanisms underlying the neuropathogenesis of HIV-1 infection, but also furnish new target(s) for the development of potential therapies in the prevention and treatment of HIV-1 disease.